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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2001-12-0235.
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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3164-3174
HEMATOPOIESIS
Identification of primary structural features that define the
differential actions of IL-3 and GM-CSF receptors
Caroline A. Evans,
Shahrul Ariffin,
Andrew Pierce, and
Anthony D. Whetton
From the Leukaemia Research Fund Cellular Development
Unit, Department of Biomolecular Sciences, University of Manchester
Institute of Science and Technology (UMIST), Manchester, United
Kingdom
Activation of human interleukin 3 (IL-3) and granulocyte-macrophage
colony-stimulating factor (GM-CSF) receptors, ectopically expressed in
FDCP-mix multipotent cells, stimulates self-renewal or myeloid
differentiation, respectively. These receptors are composed of unique
 subunits that interact with common  c subunits. A
chimeric receptor (hGM/c), comprising the extracellular
domain of the hGM-CSF receptor subunit (hGM R) fused to the
intracellular domain of hc, was generated to determine
whether hc activation is alone sufficient to promote
differentiation. hGM-CSF activation of hGM/c, expressed
in the presence and absence of the hc subunit, promoted
maintenance of primitive phenotype. This indicates that the cytosolic
domain of the hGM R chain is required for differentiation mediated
by activation of the hGM R, c receptor complex. We have previously demonstrated that the cytosolic domain confers signal specificity for IL-3 and GM-CSF receptors. Bioinformatic analysis of the IL-3 R and GM R subunits identified a tripeptide sequence, adjacent to the conserved proline-rich domain, which was
potentially a key difference between them. Cross-exchange of the
equivalent tripeptides between the subunits altered receptor function compared to the wild-type receptors. Both the mutant and the
corresponding wild-type receptors promoted survival and proliferation
in the short-term but had distinct effects on developmental outcome. The mutated hGM R promoted long-term proliferation
and maintenance of primitive cell morphology, whereas cytokine
activation of the corresponding hIL-3 R mutant promoted myeloid
differentiation. We have thus identified a region of the cytosolic
domain that is of critical importance for defining receptor specificity.
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